Pseudomonas aeruginosa pulmonary infection results in S100A8/A9-dependent cardiac dysfunction

• Published in: PLoS pathogens Vol. 19; no. 8; p. e1011573
• Main Authors: Kumar, Naresh, Pestrak, Matthew J, Wu, Qian, Ahumada, Omar Santiagonunez, Dellos-Nolan, Sheri, Saljoughian, Noushin, Shukla, Rajni Kant, Mitchem, Cortney F, Nagareddy, Prabhakara R, Ganesan, Latha P, William, Lafuse P, Wozniak, Daniel J, Rajaram, Murugesan V. S
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 25-08-2023; Public Library of Science (PLoS)
• Subjects: Abnormalities; Analysis; Antibodies; Bacterial pneumonia; Biology and Life Sciences; Bronchopulmonary infection; Cardiac arrhythmia; Care and treatment; Control; Diagnosis; Fibroblasts; Health aspects; Heart failure; Heart function tests; Identification and classification; Infections; Inflammation; Inflammatory response; Leukocytes (neutrophilic); Lungs; Medicine and Health Sciences; Microscopy; Morbidity; Mortality; Multiple organ failure; Nervous system; Neutrophils; Pathogens; Pneumonia; Prevention; Pseudomonas aeruginosa; Research and Analysis Methods; Risk factors; TLR4 protein; Toll-like receptors; Ventricle; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011573

Pseudomonas aeruginosa (P.a.) infection accounts for nearly 20% of all cases of hospital acquired pneumonia with mortality rates >30%. P.a. infection induces a robust inflammatory response, which ideally enhances bacterial clearance. Unfortunately, excessive inflammation can also have negative effects, and often leads to cardiac dysfunction with associated morbidity and mortality. However, it remains unclear how P.a. lung infection causes cardiac dysfunction. Using a murine pneumonia model, we found that P.a. infection of the lungs led to severe cardiac left ventricular dysfunction and electrical abnormalities. More specifically, we found that neutrophil recruitment and release of S100A8/A9 in the lungs activates the TLR4/RAGE signaling pathways, which in turn enhance systemic inflammation and subsequent cardiac dysfunction. Paradoxically, global deletion of S100A8/A9 did not improve but aggravated cardiac dysfunction and mortality likely due to uncontrolled bacterial burden in the lungs and heart. Our results indicate that P.a. infection induced release of S100A8/9 is double-edged, providing increased risk for cardiac dysfunction yet limiting P.a. growth.